Reaction mass of docosyl acrylate and octadecyl acrylate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

metabolism

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

no

Positive control reference chemical:

methyl methacrylate

Metabolites identified:

yes

Incubation in rat liver S9 mix

The hydrolysis rate of 2 -Propenoic acid, C16 -alkyl ester is nearly parallel with that of 2 -Propenoic acid, C18 -alkyl ester. A slow but continously increase of acrylic acid was seen after 60 min, maximum degradation of 20% until the end of exposere time.

 

Incubation in rat plasma

A decrease of 2 -Propenoic acid, C16 -18 -alkyl ester of 50 % was seen in the first 10 min, until the end of the exposure time (120 min) the decrease of the alkyl esters was 75%. A continuous increase in acrylic acid of 25% is visible over the duration of the experiment.

Reference 2

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

metabolism

Qualifier:

no guideline followed

GLP compliance:

not specified

Radiolabelling:

no

Positive control reference chemical:

methyl methacrylate

Metabolites identified:

yes

Incubation in rat liver S9 mix

The hydrolysis of 2 -Propenoic acid, C18 -22 -alkyl esters shows that the hydrolysis rate of 2 -Propenoic acid, C18 -alkyl ester, is in parallel with but a bit faster than that of 2-Propenoic acid, C20-alkyl ester and 2 -Propenoic acid, C22. Until the end of the exposure time a degradation rate of 20% was seen for 2 -Propenoic acid. C18 -22 -alkyl ester. Only a low formation of acrylic acid was seen.

Incubation in rat plasma

In the first 10 min a fast decrease of 2-Propenoic acid, C18-22 alkyl esters was seen. Until the end of the exposure time (120 min) the decrease of the 2 -Propenoic acid, C18 -22- alkyl esters was about 50%. Only a low formation of acrylic acid was seen after 60 min.

Reference 3

Endpoint:

basic toxicokinetics, other

Remarks:

Physiologically-based pharmacokinetic (PBPK) modeling

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Study period:

March - April 2023

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Objective of study:

absorption

distribution

toxicokinetics

Principles of method if other than guideline:

Physiologically Based Pharmacokinetic Models
The Simcyp Animal Simulator Version 22 Release 1 (Certara UK) was used for PBPK simulations (https://www.certara.com/software/simcyp-pbpk/ ). A whole body PBPK model, which allows for the addition of further specific organs, or a minimal PBPK model was used in simulations. (further details see attachment)

GLP compliance:

no

Type:

absorption

Results:

see attachment results

In a first step a physiologically-based pharmacokinetic (PBPK) models for 2-ethylhexyl acrylate (2EHA) and 2-ethylhexanol (2EH) were developed in the rat. Tissue distribution was predicted using a mechanistic tissue composition method (Rodgers et al., 2005, Rodgers and Rowland 2006) (Simcyp method 2). The tissue distribution models were parameterised using estimates of the log of the octanol-water partition coefficient (LogP) and predicted values for fraction unbound (fu) and blood:plasma ratio (B/P). For 2EH, a minimal PBPK model was parameterised with a single adjusting compartment to capture the biphasic time course of the compound in blood and for 2EHA, a full body PBPK model was used.

Metabolism of 2EHA to 2EH was parameterised using in vitro metabolism data in rat liver microsomes and rat plasma. Clearance of total 2EH-related radioactivity was included in the model based on urinary and expired CO2-reported mass balance data after intravenous (IV) dosing. The developed 2EH PBPK model in the rat was able to show close agreement between observed and predicted plasma concentration-time data from orally administered 2EH (70.6 mg/kg body weight (BW)) when assuming administration as a solution with precipitation and first pass intestinal extraction (20%). Considering the high predicted permeability and observed high intrinsic solubility, predicted fraction absorbed (fa) was 1.00 and was insensitive to critical supersaturation ratio (CSR) and precipitation rate constant (PRC) values. The 2EH model was subsequently modelled as a primary metabolite of 2EHA following oral 2EHA administration (100 mg/kg BW). When simulated as a solution with precipitation, considering intrinsic solubility of 2EHA, the CSR of 10 and a PRC of 0.3 1/h were found to capture observed fa (approximately 0.90) in line with in vivo data.

The same assumptions of absorption model settings were applied to 7 chemically related acrylate esters with varying chain lengths, lipophilicity, solubility and physical states. Chemicals with a solid physical state at 20°C were assumed to be administered as a solid (requiring the compound to dissolve in the intestine before absorption can take place). Predicted fa ranged from 0.0001 to 1.00. In general, the larger compounds (chain length >14) with higher log octanol/buffer partition coefficient (LogPo:w) (>8), lower intrinsic solubility (<2x10-6 mg/mL) and a solid physical state at 20oC resulted in lower predicted fa values.

Predicted fa in rat for a series of chemically related acrylate esters with varying chain lengths.

Absorption predictions were based on the settings utilised in a PBPK model built to describe absorption and exposure of 2-ethylhexyl acrylate and its metabolite 2-ethyl hexanol. :

Compound Name	Side Chain Length	LogPow	Aqueous Solubility (mg/ml)	Physical state at 20°C	Predicted Rat fa
Ethyl acrylate	2	1.18	1.00E-02	Liquid	1.00
2 -Ethylhexanol		2.9	9.00E-01	Liquid	1.00
2 -Ethylhexyl acrylate	8	4	1.00E-02	Liquid	0.91
Dodecyl acrylate	12	6.13	2.00E-04	Liquid	0.81
Tetradecyl acrylate	14	7.11	2.00E-06	Liquid	0.77
Hexadecyl acrylate	16	8.09	1.19E-06	Solid paste	0.0150
Octadecyl acrylate	18	9.08	2.61E-10	Solid paste	0.0001
Icosyl acrylate	20	10.06	2.70E-08	Solid paste	0.0022
Docosyl acrylate	22	11.04	1.50E-09	Solid	0.0006

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption:

All members of the category are not expected to be readily absorbed by oral, inhalation and dermal routes based on the experimental data and predictions from physico-chemical properties. The available repeated dose toxicity studies for oral route/reproductive toxicity show that the long-chain acrylate esters, either as parents and/or their metabolites, are not likely absorbed based on the lack of significant systemic effects observed.

In an in silico study, the expected low gastrointestinal and systemic uptake was confirmed in an in silico PBPK modelling. For octadecyl acrylate; icosyl acrylate and docosyl acrylate the predicted fraction absorbed was 0.0001, 0.0022, and 0.0006, respectively.

 

Based on the molecular weights varying from 240 to > 350 g/mol, the high log Pow between 6.13 to 11.04 and very low water solubility values, the long-chain acrylate esters are not very likely to be absorbed in the gastrointestinal (GI) tract. The high log Pow indicates that the substances will not diffuse well across plasma membranes. In addition, gastro-intestinal absorption will not be triggered by passage via passive diffusion through aqueous pores or carriage with the bulk passage of water, which is favoured for small (molecular weight < 200 g/mol), water soluble substances. Therefore, only very low concentrations of these substances are bioavailable. The substances may be taken up by micellular solubilisation since this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), particularly those that are poorly soluble in water. Overall, limited gastrointestinal absorption is expected for the target substance and the source substances based on their physicochemical properties. Moreover, almost no systemic effects were seen in acute and repeated dose toxicity studies after oral administration of mixture of C12-14 acrylates or mixture of C18-22 acrylates demonstrating and supporting that long-chain alkyl esters are not very well absorbed in the gastrointestinal tract, and if absorbed reveal a low systemic toxicity.

 

Higher acrylate esters exhibit a low volatility (vapour pressure of hPa). Therefore, only a very minimal amount of the substance is available for inhalation and thus, absorption by inhalation can be almost excluded. Moreover, absorption will be limited due to the low water solubility and high Pow of the substances. In addition, fine dust is not formed by this compound. Consequently, inhalation exposure due to fine dust or particles is also unlikely.

 

The long-chain acrylate estersare liquid or solid with very low water solubility (< 0.1 mg/L) and molecular weights between 240 and 350 g/mol, therefore dermal uptake from the stratum corneum into the epidermis is likely to be low. With log Pow > 6.5 the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. In addition, the substances showed no effects when tested for acute dermal toxicity or skin irritation.

These characteristics are in line with information obtained with the structural related substance Dodecyl methacrylate (C12, also known as Lauryl methacrylate): Experiments on this structural related substance with rat skin have demonstrated that the long-chain methacrylate esters in principle are dermally absorbed at very low amounts (0.26 % over 26 h). As a tendency confirmed with experiments on esters up to a chain length of C8, absorption decreased with increasing ester chain length. Due to the slow diffusion as well as the metabolic competency of the skin, the ester underwent complete hydrolysis to methacrylic acid and the long-chain alkyl alcohol. It is suggested that the rate of hydrolysis is more rapid than its absorption across the dermal region of the skin. It can be concluded that the ester is completely metabolized during the dermal absorption process (Jones, 2002). Furthermore, dermal absorption modelling performed with Dermwin (EPIsuite) also shows such a trend.

Dermal absorption rates for long-chain acryl esters generated with Dermwin model (EPIsuite).

 

Substance	Absorption rate (mg/cm2)	Kp (cm/h)
C12	0.00042	0.831
C14	0.000242	0.579
C16	0.000141	0.403
C18	0.0000802	0.28
C20	0.0000454	0.195
C22	0.0000256	0.136

 

Based on the physicochemical properties of higher acrylate esters they are unlikely to be widely distributed systemically throughout the extracellular compartments of the body after absorption. Particularly due to the low water solubility and the high log Pow values, a long biological half-life in tissues might be expected, but is almost excluded due to the poor absorption and the metabolic cleavage. Thus, the target substance and the source substances have no bioaccumulation potential and only a limited amount of any of these substances come into consideration for distribution into blood or plasma and accumulation in organs and tissues. Furthermore, the experimental data from the repeated dose toxicity study with C12-14 acrylate ester mixture has not shown any significant organ-specific toxicity which further supports the hypothesis of poor distribution throughout the body.

 

Metabolism:

This category is based on the hypothesis that the acrylate esters have similar toxicological properties and they have a common rapid metabolism pathway described by two primary routes: carboxylesterase mediated hydrolysis of the ester linkage to acrylic acid and the corresponding alcohol; and conjugation of AA-ester with glutathione.  

Primary hydrolysis products

 

Acrylate esters	Primary hydrolysis products
2-Propenoic Acid, C12-C14 alkylesters (Laurylacrylate 1214)	Acrylic acid, dodecanol and tetradecanol
Dodecyl acrylate (C12)	Acrylic acid and dodecan-1-ol
Tetradecyl acrylate (C14)	Acrylic acid and tetradecan-1-ol
2-Propenoic acid, C16-C18 alkylesters (Stearylacrylate)	Acrylic acid, hexadecan-1-ol and octadecan-1-ol
Hexadecyl acrylate (C16)	Acrylic acid and hexadecan-1-ol
Octadecyl acrylate (C18)	Acrylic acid and octadecan-1-ol
2-Propenoic acid, C18-22-alkyl esters	Acrylic acid, octadecan-1-ol and docosan-1-ol
Icosyl acrylate (C20)	Acrylic acid and icosan-1-ol
Docosyl acrylate (C22)	Acrylic acid and docosan-1-ol

 

 The alcohols associated with the esters being formed after hydrolysis are dodecan-1-ol (CAS No. 112-53-8), tetradecan-1-ol (CAS No. 112-72-1), hexadecan-1-ol (CAS No. 36653-82-4),octadecan-1-ol(CAS No. 112-92-5), docosan-1-ol (CAS No. 661-19-8), and icosan-1-ol (CAS No. 112-92-5 ). These alcohols are not considered to impact on the read-across approach within the category. Due to the rapid metabolism of the acrylate esters as demonstrated in the in vitro assays, the systemic toxicity exerted from the parental acrylate esters is also considered to be of minimal relevance (Roos, 2015).

 

However, the available toxicological studies of the category members for systemic toxicity endpoints suggest the similarity in toxicological properties. Therefore, any potential variation in toxicity associated with differences in the ester chain length is considered to be negligible. It is therefore concluded that AA is the common product of metabolism that is partly responsible for systemic toxicity for all substances within the category.

 

The major route of metabolism of acrylate esters has been shown to involve the rapid cleavage of the ester bond by carboxylic esterases (Figure 2; ECETOC, 1998; WHO, 1997), resulting in internal exposure to AA. Following carboxylesterase-catalysed hydrolysis to AA and the corresponding alcohol, a subsequent metabolic pathway involves metabolism of AA to carbon dioxide (CO2) via the propionate degradation pathway. The respective alcohols are metabolised via either a catalase peroxidative pathway or the alcohol dehydrogenase pathway. There is a trend towards increasing half-life of the esters in blood with increasing alcohol chain length (Roos, 2015). But systemically absorbed parent esters will be effectively removed during first pass through the liver resulting in their relatively rapid elimination from the body.

 

Half-lives and degradation rates for acrylate esters in presence of rat S9 fraction or plasma (Roos, 2015)

Substance	CAS No.	S9 Rat  (t1/2min.)	Plasma  (t1/2min.)
MA	96-33-3	-	34.62
EA	140-88-5	1.40	-
nBA	141-32-2	0.84	8.45
iBA	106-63-8	0.74	8.15
tBA	1663-39-4	-	-
2EHA	103-11-7	1.15	6.48
2-Propenoic Acid, C12-C14 alkylesters	84238-60-8	22.5 - 34,78	14.93 - 21.44
Dodecyl acrylate (C12)	2156-97-0	ND	ND
Tetradecyl acrylate (C14)	21643-42-5	ND	ND
2-Propenoic acid, C16-C18 alkylesters	90530-21-5	34.26 - 68.96	70.00-79.75
Hexadecyl acrylate (C16)	13402-02-3	ND	ND
Octadecyl acrylate (C18)	4813-57-4	ND	ND
2-Propenoic acid, C18-22-alkyl esters	85085-17-2	-	-
Icosyl acrylate (C20)	48076-38-6	ND	ND
Docosyl acrylate (C22)	18299-85-9	ND	ND

 

 

Acrylate esters are also expected to undergo conjugation with GSH to form thioesters (Frederick et al., 1992), with the main urinary conjugate identified as N-acetyl-S-(2-carboxyethyl)cysteine.The conjugates are then converted to mercapturic acids and excreted in the urine (Silver and Murphy, 1981; Miller, 1981).Inhibition of the hydrolytic pathway with a carboxylase inhibitor results in increased metabolism via the GSH conjugation route.Some minor impact is exerted by the positive inductive effect of the alcohol sub-group, but the incremental impact on electrophilicity rapidly decreases with increasing alcohol chain length. Therefore, for direct electrophilic reactions the alcohol group will only have a minor, rather monotonic influence with increasing chain length.

McCarthy et al. (1994) reported that increased alcohol chain length moderately affected the apparent second-order rate constant for the spontaneous reaction of acrylate esters with GSH in the in vitro study but did not affect potency relative to cellular GSH depletion. The structural alerts generated using QSAR Toolbox v4.3 show the similarity in electrophilic reactivity for all the category members.

Also, the low absorption of the long-chain acrylate esters can be considered a limiting factor for the formation of thioestersand GSH depletion.

Generally, metabolism will render the molecule more polar and harmless, leading to faster excretion. No conversion into a metabolite that is more toxic than the parent is expected as no increases in toxicity were noted in the presence of metabolic activation during the in vitro tests.